Histone deacetylase 3 (HDAC3) participates in the transcriptional repression of the p16^INK4a gene in mammary gland of the female rat offspring exposed to an early-life high-fat diet

Maternal exposure to environmental agents throughout pregnancy and lactation may affect offspring's mammary gland growth and alter the epigenome. This may predispose the offspring's mammary glands to be more susceptible to carcinogenesis. The purpose of this study was to examine the effect of a maternal high-fat diet on the regulation of p16^INK4a gene expression in the mammary gland of rat offspring. Timed-pregnant Sprague-Dawley rats were fed one of the two diets, a control (C, 16% of fat) or a high fat (HF, 45% of fat) diet, throughout gestation and lactation and sacrifced at 12 weeks of age. Compared with C, HF offspring showed a decrease of p16^INK4a gene expression in the mammary gland at both mRNA and protein levels. Chromatin immunoprecipitation (ChIP) assay demonstrated that the downregulation of p16^INK4a transcription in HF ofspring was associated with reduced acetylation of histone H4 and increased recruitment of histone deacetylase 3 (HDAC3) within the p16^INK4a promoter region, but was not associated with acetylation of histone H3 or HDAC1. Methylated DNA immunoprecipitation (MeDIP) did not detect diferences in methylation at diferent regions of the p16^INK4a gene between C and HF ofspring. We conclude that maternal high fat exposure represses p16^INK4a gene expression in the mammary gland of ofspring through changes of histone modifcations and HDAC3 binding activity within the regulatory regions of the p16^INK4a gene.